Neurochemistry international ( IF 4.2 ) Pub Date : 2020-08-25 , DOI: 10.1016/j.neuint.2020.104842 Yan Li 1 , Li-Min Zhang 1 , Dong-Xue Zhang 2 , Wei-Chao Zheng 1 , Yang Bai 1 , Jing Bai 1 , Lan Fu 3 , Xu-Peng Wang 1
Objective
Emotional disturbances characterized by depression and anxiety among survivors of traumatic brain injury (TBI) impact the quality of life severely. Currently, there is a lack of effective drug treatment for neurodegeneration induced by TBI, mainly due to failed efficacy of compounds such as corticosteroids, calcium channel blockers, and excitatory amino acid inhibitors. Thus, we sought to continue with our investigation on CORM-3, a water-soluble exogenous carbon monoxide-releasing molecule with excellent anti-inflammatory actions employed in a previous study using a rat model of combined TBI with hemorrhage shock and resuscitation (HSR).
Methods
Rats were administrated with CORM-3 after induction of TBI and HSR and examined depressive and anxiety-like behaviors, along with cerebral function employing functional magnetic resonance imaging (MRI) 30-days post-trauma. Also, the following variables were measured: 1) neuronal pyroptosis and apoptosis 24 h post-trauma, 2) the roles of PKG-ERK1/2 signaling pathways with the use of the protein kinase G (PKG) specific inhibitor, KT5823.
Results
CORM-3-treated rats displayed significant ameliorated depression- and anxiety-like behaviors, improved cerebral blood flow, and fractional anisotropy (FA), showed less neuronal pyroptosis and apoptosis in the amygdala, and upregulated the phosphorylation of Vasodilator-stimulated phosphoprotein (VASP) and ERK1/2. However, CORM-3 neuroprotective effects against trauma were only partially reversed by KT5823.
Conclusion
CORM-3 ameliorated the emotional deficits and neuronal death induced in the amygdala post-TBI and HSR rat model, and PKG-ERK1/2 signaling might be implicated in the underlying mechanism.
中文翻译:
CORM-3 可改善杏仁核中的神经变性并改善合并创伤性脑损伤和失血性休克的大鼠模型中的抑郁和焦虑样行为。
客观的
创伤性脑损伤 (TBI) 幸存者以抑郁和焦虑为特征的情绪障碍严重影响了生活质量。目前,由于皮质类固醇、钙通道阻滞剂和兴奋性氨基酸抑制剂等化合物的疗效不佳,TBI 引起的神经变性缺乏有效的药物治疗。因此,我们试图继续对 CORM-3 进行研究,CORM-3 是一种水溶性外源性一氧化碳释放分子,在先前的研究中使用了联合 TBI 与出血性休克和复苏 (HSR) 的大鼠模型,具有出色的抗炎作用.
方法
在诱导 TBI 和 HSR 后给大鼠注射 CORM-3,并在创伤后 30 天使用功能性磁共振成像 (MRI) 检查抑郁和焦虑样行为以及脑功能。此外,还测量了以下变量:1) 创伤后 24 小时的神经元焦亡和细胞凋亡,2) 使用蛋白激酶 G (PKG) 特异性抑制剂 KT5823 时 PKG-ERK1/2 信号通路的作用。
结果
CORM-3 治疗的大鼠表现出显着改善的抑郁和焦虑样行为,改善脑血流量和分数各向异性 (FA),显示较少的杏仁核神经元焦亡和凋亡,并上调血管扩张剂刺激的磷蛋白 (VASP) 的磷酸化) 和 ERK1/2。然而,KT5823 仅部分逆转了 CORM-3 对创伤的神经保护作用。
结论
CORM-3 改善了 TBI 后杏仁核和 HSR 大鼠模型中诱导的情绪缺陷和神经元死亡,并且 PKG-ERK1/2 信号可能与潜在机制有关。